Week 4 Flashcards
What do early pro B cells express? Intermediate? Late?
Early- TdT alone
Intermediate- both TdT and B220
Late- B220 and down regulated TdT
What 2 cytokines allow inflammatory cell recruitment?
IFN-gamma
TNF-alpha
What molecule modulates exchange for CLIP and antigenic peptide in MHC class 2 formation? What molecules blocks until acidic conditions?
HLA DM facilitates exchange
-HLA DO blocks DM (DO is only expressed in B cells and in thymus- helps DM only work in late endosome)
What enzyme is mutated in XLA immunodeficiency?
Bruton’s tyrosine kinase (Btk)
What ligand and receptors are mutated in Common Variable Immunodeficiency (CVID)?
CD40 ligand on T cells, B cell surface receptor CD19, activated T cell co-stimulatory molecules ICOS and TACI
Binding of what receptor on the T cell with B7 on APC is stimulatory? inactivating?
- stimulatory= B7 with CD28
- inactivating= B7 with CTLA-4
What cells express MHC class 1? MHC class 2?
- MHC class 1- most cells in body (except RBCs)
- MHC class 2- professional APCs (DCs, macrophages, B cells)
When do DCs, macrophages, B cells express MHC-class 2? (constantly, induced, etc)
- DCs: constituitively express MHC-2 (also always express B7)
- Macrophages: must be activated to express MHC class 2 and co-stimulatory molecules
- B cells: constitutively express Class 2; must be activated to express co-stimulatory molecules
What MHC class is loaded by the cytosolic pathway?
-MHC class 1 (synthesized in RER; TAP1/2 to enter ER)
What MHC class is loaded by the endocytic pathway?
-MHC class 2
What is the normal ratio of CD4: CD8 T cells in the body?
~65% CD4 and ~35% CD8
What age does MHC class 1 deficiency affect patient? Susceptible to what infections?
- young (age 4)
- susceptible viral infections: influenza, EBV
What age does MHC class 2 deficiency affect patient? (inherited autosomal recessive) Susceptible to what infections?
- onset 6 months
- mild form SCID (makes few T cells)
- elevated WBCs (esp. neutrophils and lymphocytes)
- low CD4+ T cells
- no HLA-DQ or HLA-DR being formed
- susceptible to pyogenic and opportunistic infections
How does classic SCID differ from milder form in case?
- classic SCID: no T cells responding to any antigen
- milder form: T cells could be activated in vitro by PHA
Is there a treatment for MHC class 1 deficiency? Class 2?
- MHC class 1 deficiency- no
- MHC class 2 deficiency- hematopoietic stem cell transplant
What cytokine induces expression of MHC class 2 molecules on APC?
Interferon- gamma
What are the cytokines required for B cell development?
- IL-7: promotes B cell lineage development
- Blys: survival of pre-immune B cells
- IL4, IL3, L-BCGF: initiating B cell differentiation
Transitional immature B cells: Which receptor on surface for TI-1? TI-2? where do they help B cell go?
- TI-1: transitional phase with IgM (T cell zone); negative selection
- TI-2: transitional phase with IgM and IgD (go to follicle); positive selection
T-independent B cell activation: Which antigens are TI-1 antigens? TI-2?
-many TI antigens are PAMPs (recognized by TLRs)
- TI-1: bacterial cell wall components; LPS (TLR4 or BCR)
- TI-2: large polysaccharide molecules with repeating antigenic determinants (Ficoll, dextran, polymeric bact. flagellin, poliomyelitis virus)
- activate B1 B cells
Which TLR causes nonspecific (polyclonal) activation?
Which receptor causes specific (clonal) activation?
- TLR4= polyclonal
- BCR= clonal
- only IgM is produced
How do B1 B cells bind Type 2 TI antigen? What type of activation?
- crosslinking BCR
- specific (clonal) activation
- mostly IgM produced
Expression of what CD molecule can identify B-1 cells?
-CD5
Where do B and T cells that recognize each other go? What does B cell need to express to survive?
- go to germinal centers
- B cell must express Bcl-2 (to protect itself from apoptosis)
What does CD44 do in T cell development?
-CD44 is required for re-localization to the thymus
What stage in T cell development expresses CD44? CD25? CD3? CD4? CD8? CD117 (c-Kit)?
- CD44- DN1 and DN2
- CD25- DN2 and DN3
- CD3- DN3 and beyond
- CD4 and CD8- DP
- CD4 or CD8- single positive
- CD117 (c-Kit)- stem cell, lymphoid progenitor, DN1, DN2
Which polarizing cytokines induce Treg cells? master transcriptional regulator?
- IL2, TGF-beta
- FOXP3
Which polarizing cytokines induce TH 17 cells? master transcriptional regulator?
- IL1, IL6, IL23, TGF-beta
- ROR-gamma t
Which polarizing cytokines induce TH 2 cells? master transcriptional regulator?
- IL4
- GATA3
Which polarizing cytokines induce T-FH cells? master transcriptional regulator?
- IL6, IL21
- Bcl-6
Which polarizing cytokines induce TH-1 cells? master transcriptional regulator?
- IL12, IFN-gamma, IL18
- T-Bet
What effector molecules are produced by CD8+ cytotoxic T cells? NK cells?
-how do the molecules work?
- CD8+ CTLs: cytotoxins (perforins and granzymes), IFN-gamma, TNF, Fas ligand
- NK cell: cytotoxins (perforins and granzymes), IFN-gamma, TNF, Fas ligand
- both do cytotoxic granule release and FASL-FAS interactions
What cell surface proteins of CD4+ T cells and APCs are important in “licensing” APC for cross-presentation of antigen?
- licensing of APC requires interaction with a CD4+ Th1 cell or direct interaction with a pathogen- TLR molecule
- licensing of DCs occurs by: 1) CD40L + helper T cell, or 2) pathogen (via TLR)
Mechanisms of CTL killing:
- Perforin (form pore) and granzyme(activate apoptosis by cleaving caspases) secretions
- Fas ligand (cleave caspases)
- TNF production and secretion
NK cells produce IFN-gamma- what effects does this have in cell production?
- IFN-gamma tilts immune response toward Th1 by inhibiting Th2 cells and inducing IL-12 production by macrophages and DCs
- IFN-gamma can activate M1 (angry) macrophages and NK cells
What 2 types of receptors can either activate or inhibit NK cells?
- Lectin-like receptors (bind proteins rather than polysaccharides)
- Immunoglobulin-like receptors (KIR= killer cell immunoglobulin-like receptors): bind to most MHC class 1 molecules
Which KIR family receptors work in inhibitory fashion? what ligands on potential target cells?
- KIR2DL1: HLA-C2
- KIR3DL1: HLA-Bw4
- KIR3DL2: HLA-A3 and A111
- KIR2DL2/3: HLA-C1
Only activating = KIR2DS1: HLA-C2
Which lectin-like family receptors work in inhibitory fashion? what are ligands they bind?
-CD94-NKG2A: HLA-E
all others are activating
What is the general process and cells involved with antibody-dependent cell mediated cytotoxicity (ADCC)?
- Effector cells: NK, macrophages, monocytes, neutrophils, eosinophils
- Effector cells bind antigen via Ab (through Fc receptor)
- Killing: mediated by cytolytic enzyme release by macrophages, neutrophils, eosinophils
- TNF release by NK cells, monocytes, macrophages
- Perforin release by NK cells and eosinophils
- Granzyme release by NK cells
What are the genetic abnormalities in Acute Promonocytic Leukemia (APML)?
- inv(16); 11q23
- treat promptly with hydroxyurea, leukopheresis, chemo
- DIC with APML (M3)
With acute leukemia, what lab test should you run to test for choromosomal abnormalities?
-Cytogenetics
favorable risk= t(8;21), t(16;16); t(15;17); unfavorable risk= del5, del7, trisomy 8, 11q23
What new AML drug inhibits Flt-3 receptor tyrosine kinase?
- Quizartinib
- notable SE: QTc prolongation (watch EKG)
What new AML drug targets CBF (core binding factor)?
- Dasatinib
- c-Kit overexpression in CBF + AML
What diagnosis is characteristic of CD5+ CD23- cyclinD1+?
-Mantle cell lymphoma (aggressive NHL)
What is the difference between CLL and SLL (small lymphocytic leukemia)?
-SLL is only in tissues (tissue phase of CLL)
What are 2 poor prognostic factors of CLL? One good prognostic factor?
- worse: CD38+ or ZAP-70+
- better prognosis: CD38-
What drug causes loss of reflexes in 100% patients? (reflex loss is how drug dosage is determined enough)
-Vincristine (and Vinblastine?)
Which plant alkaloid is not susceptible to MDR resistance?
-Ixabepilone
What are the 2 immunosuppressive antibiotics used to prevent rejection after bone marrow transplants?
-Cyclosporine and Tacrolimus
What target do Rituximab, Ibritumomab, and Tostitumomab bind? TU?
- CD20
- B cell NHL
What target does Gemtuzumab bind? TU?
- CD33
- No longer used (removed from market?
What target does Alemtuzumab bind? TU?
Specific toxicity?
- CD52
- B cell lymphocytic leukemia (B-CLL)
- can cause cough and chest tightness
What target does Denileukin-Diftitux bind? TU?
- cells expressing IL-2R
- cutaneous T-cell lymphoma
What cytokine can cause hand/foot syndrome, thrombocytopenia, shock, respiratory distress, fatal hypotension, and possible coma?
-Interleukin-2
What cytokine decreases angiogenesis, decreases cell division, increased MHC-class 1 expression on tumor cells, and has possible SE of depression?
- Interferon alpha
- other SEs: flu like Sx, hypotension, BMS
Which cytokine has such a short half life it must be given IA, and has SEs of flu like Sx and possible hemorrhagic necrosis?
-Tumor necrosis factor- alpha
Which hematopoietic agent increases production of neutrophils by stimulating G-CSF?
-Filgrastim
Which hematopoietic agent increases production of granulocytes, eosinophils, basophils, and monocytes by stimulating GM-CSF?
-Sagramostim
Which 2 hematopoietic agents increase platelet production?
- Interleukin 11
- Thrombopoietin
What do Dasatinib, Imatinib, and Nilotinib target?
- Bcr-Abl
- treat CML
What do Cetuximab, Erlotinib, Gefitinib, Lapatinib, and Panitumumab target?
-EGFR (a tyrosine kinase)
What do Lapatinib and Trastuzumab target?
- HER2 (a tyrosine kinase)
- treat breast cancer
toxicity: ventricular dysfunction/ CHF (ErbB2)
What do Pazopanib, Sorafenib, and Sunitunib target?
PDGF-R and VEGF-R (angiogenesis)
What is L-Asparaginase used to treat? Is MTX given before or after when used together?
- childhood ALL
- must give MTX first to have synergy
Which drug is competitive inhibitor of 26S proteosome? TU? Toxicities?
- Bortezomib
- used for multiple myeloma
- Toxicity: thrombocytopenia, anemia, neutropenia, peripheral neuropathy
Which drug is an HDAC inhibitor? Toxicities?
- Vorinostat (suppression of suppression to cause apoptosis)
- Toxicity: PE, DVT, thrombocytopenia, anemia; interaction with Warfarin, N/V, diarrhea, hyperglycemia, dysgeusia
What are the 3 differentiating agents? TU?
-Tretinoin
-Arsenic Trioxide (prolonged QT/ arrhythmias)
-Bexarotene (pancreatitis from hyperlipidemia)
Induce tumor cell differentiation leading to apoptosis
TU: Acute promyelocytic leukemia (APL)
Which tyrosine kinase do Dasatinib, Imatinib, Nilotinib, and Sunitinib target? Cancer type?
- c-kit
- GIST (GI stromal tumors)
- Dasatanib also targets Src (anti-metastatic in epithelial derived tumors)
What is the mechanism of action for Erlotinib and Gefitinib?
- competitive antagonists of ATP binding site of epithelial growth factor receptor (EGFR) tyrosine kinase
- epithelial- derived cancers
What are unique SE risks for Abl tyrosine blockers (Dasatinib, Imatinib, and Nilotinib)?
- CHF and decreased left ventricular ejection fraction (causing shortness of breath, palpitations, fatigue) and/or MI
- Abl tyrosine kinases are necessary for normal heart function
What is a unique toxicity for Erlotinib and Gefitinib?
-interstitial pneumonia (which can be fatal)
What do Everolimus and Temsirolimus block?
-mTOR
What does Bevacizumab block?
-VEGF
Which cytokine induces interferon-gamma which increases inducible protein 10? SE: GI and liver function effects (side effects decrease with time)
IL-12
-angiogenesis inhibition
Which cytokine decreases cell division and increases MHC class 1 expression on cancer cells? Also decreases FGF production?
- Interferon-alpha
- depression is common side effect
- anti-angiogenesis
Which drug is anti-VEGF? Unique SEs: GI perforation, wound dehisence, hemoptysis?
- Bevacizumab
- anti angiogenesis
What do Pazopanib, Sorafinib, and Sunitinib do? Unique targets for each? TU?
- all three target VEGF-R and PDGF-R
- Sorafinib- also targets Raf
- Pazo and Suni- also target c-kit
- TU: renal cell carcinoma
What are specific SEs unique to Pazopanib, Sorafinib, and Sunitunib?
- Pazopanib: hepatotoxicity, hemorrage, GI performation, hypertension
- Sorafinib: hemorrhage, hypertension
- Sunitinib: hand-foot syndrome, skin discoloration
What drug is used to treat Hansen’s disease, multiple myeloma, and off label use for AIDs? SE?
- Thalidomide
- N/V, rashes, peripheral neuropathy, increased risk DVT (treat with Warfarin right away)
- severe birth defects (phocomelia- malformed intestines, hearing defects, ocular and retinal defects, deformed limbs)
What is an example of recruitment (used to treat AML)?
-Daunorubicin and Cytarabine
What are the 4 Chronic Myeloproliferative disorders? main cells in each?
- CML- neutrophils
- Polycythemia vera- red cells
- Essential thrombocythemia- platelets
- Myelofibrosis- everything
Which chronic myeloproliferative disorder results from mutated Jak2 or too much EPO (secondary)?
Polycythemia Vera
Which chronic myeloproliferative disorder can present with either bleeding or thrombosis?
Essential Thrombocythemia
Which chronic myeloproliferative disorder has teardrop red cells?
Chronic Myelofibrosis
What molecular event initiates CML?
- translocation t(9;22)/ Philadelphia chromosome
- BCR-ABL fusion protein
What are the activating changes in BCR-ABL1?
- coiled-coil domain is added from BCR (promotes dimerization, necessary for activation)
- Myristate attachment site lost from ABL1 (necessary for auto-inhibition of ABL1 TK activity)
- Tyrosine-177 is added from BCR, phosphorylation creates new binding site for intracellular signaling proteins
What does phosphorylation of Y177 on BCR fusion gene do? Why is it unique?
- causes dysregulated proliferation and protection from apoptosis
- BCR normal gene is not a TK (not P)
In oncogenic signaling, BCR-ABL1 kinases activate what pathway in the cell?
-Jak2 to Stat5 (causes transcription of anti-apoptotic genes even when GM-CSF receptor not activated
What disease is the TRAP stain positive for?
Hairy Cell leukemia
What is the most common cause of lymphadenopathy? most common malignant cause?
- most common a benign reaction to infection
- malignant: most likely metastatic carcinoma
What type of macrophages are usually found in normal germinal centers?
Tingible body macrophages
What cell markers are found in Small Lymphocytic Lymphoma (same as CLL)?
- B cell lesion but also CD5+
- small mature lymphocytes
What disease can be associated with Helicobacter pylori infections?
- Malt lymphoma (type of Marginal Zone Lymphoma)
- give antibiotics
What disease is associated with t(11;14)? (cyclinD and IgH translocation)
-Mantle Cell lymphoma
What disease is associated with t(14;18)? (IgH and bcl-2)
- Follicular lymphoma
- “butt” cells
- CD20 positive
What disease is a T cell lymphoid process that has cerebriform lymphocytes, skin lesions, and blood involvement?
-can be mistaken for eczema or psoriasis
-Mycosis Fungoides/ Sezary Syndrome
What disease is commonly a T-lyphoblastic lymphoma often in teenage male with mediastinal mass? (lymphoblasts in diffuse pattern)
- Lymphoblastic Lymphoma
- 2 types: B and T
- same as ALL
Which disease is associated with t(8;14) (c-myc and IgH)
- Burkitt Lymphoma
- starry-sky pattern
- child with fast growing extranodal mass
What disease has B-cell origin with popcorn cells?
Nodular L-P Hodgkin lymphoma
- good prognosis (early stage)
- asymptomatic young male with cervical lymphadenopathy
Which drug is the most potent anti-TNF-alpha agent known?
-used to treat multiple myeloma
-Thalidomide
What type of biopsy is needed for lymphoma diagnosis?
excisional biopsy
What is the criteria for stagin lymphoma? Stage 1-4
Stage 1: single location
Stage 2: 2 or more locations; same side of diaphragm
Stage 3: both sides diaphragm
Stage 4: involving organs
Which is the most common NHL in adults?
Diffuse large B cell Lymphoma (DLBCL)
-treated with CHOP
Which drug specifically targets CD20?
Rituximab (really helped lymphoma treatments)
What changes worsen and improve CLL prognosis?
- worse: loss of TP53 (17p)
- favorable: 13q14.3 (13q)
What drugs should you NOT give if you suspect lymphoma?
steroids (may shrink it before you know what it is) - need excisional biopsy
